Recent Patents on Endocrine, Metabolic & Immune Drug Discovery - Volume 6, Issue 1, 2012

Recent Patents on Endocrine, Metabolic & Immune Drug Discovery is an important addition to the ‘Recent Patent’ journal series published by Bentham Science Publishers. The journal publishes review and research articles and thematic issues on recent patents reviewed in the field. The scope of the journal covers therapeutic targets/ agents associated with endocrine, metabolic and immune drug discovery; novel drugs/ hormone for the treatment of diabetes, cardiovascular, obesity, endocrine glands and hormones , and related areas. In this issue, Cheung and Tang discusses the role of adrenomedullin in many biological systems particularly cardiovascular, endocrine, immune, musculoskeletal infection, reproductive, neuroendocrine and renal functions. The recent patents cited in this article claims the use of peptide from human pheochromocytoma tissue in diabetes and cardiovascular diseases and blocking angiogenesis in cancers. Adrenomedullin also acts as an endocrine biomarker in diabetes and cardocascular diseases and also acts as growth factor in proliferation of osteoblasts. The diagnostic applications of adrenomedullin was also discussed. Investigations on in vivo studies in subjects with metabolic diseases at increased cardiovascular risk by polyphenol rich extracts is published by Broekhuizen et al. [1].The results showed anti-inflammatory effect by reducing inflammatory chemokines monocyte chemoattractant protein 1 (MCP-1) and macrophage migration inhibitory factor and other factors. Recently, Banegas et al. have reported the studies in patients with metabolic syndrome [2], while Chapman presented the effects of a new statin, pitavastatin in atherogenic dyslipidemia on both apolipoprotein B-containing and apolipoprotein A1- containing lipoprotein components of the atherogenic lipid profile (low-density lipoprotein-cholesterol, low-density lipoproteincholesterol, and high-density lipoprotein-cholesterol levels). The clinical trials were also conducted [3]. Potential use of a novel basal insulin analog- Degludec was reviewed with related patents by Kalra et al. The preference of Degludec over existing human basal insulins was studied for the treatment of type 2-diabetes and type -1 diabetes. Formulations, pharmacodynamics and pharmacokinetics have also been reported. Combined administration of a DPP-4 inhibitor and long-acting insulin (insulin degludec, insulin glargine, insulin detemir, which are insulin analogs, and ultralente insulin) was claimed to inhibit metabolic diseases [4]. The combination therapy comprising glucagon-like peptide-1 receptor agonist and a dipeptidyl peptidase-4 inhibitor (linagliptin) was also claimed to be effective in hyperlipidemia, hypertension, atherosclerosis, hyperglycemia, overweight and obesity [5]. WO2011134471 relates to the treatment of type 1 or type 2 diabetes, diabetes- related diseases or disorders with compositions of new peptide conjugate comprising covalently coupled/linked specific exendin and gastrin peptide, or glucagon-like peptide and gastrin peptide or in combination with insulin or an analog (Degludec or others) and a DPP-IV inhibitor [6]. Meneghini and Miranda-Palma discusses the management of type 1 and 2 diabetes with novel ultra-long-acting basal insulin degludec [7]. Current literature review for the management of type 2 diabetes and micro-and macrovascular complications such as nephropathy, neuropathy, retinopathy, and cardiovascular disease associated with type 2 diabetes complications was discussed by [8]. A new target Microsomal triglyceride transfer protein (MTP) inhibitors for treating dislipidemia was identified by Raval et al. The mechanical properties of MTP inhibition with Phase 2 & 3 clinical trials studies of SLX-4090 and Lomitapide (AEGR 733) and recent patented claims were presented by the authors. The promising results of LDL cholestrol lowering property by MTP were established in human trials....

Adrenomedullin is a peptide initially isolated from pheochromocytoma. It has a wide distribution and has multiple actions in many systems including the cardiovascular, renal, endocrine, reproductive, immune, nervous and musculoskeletal systems. This is reflected in the patents. These cover the use of adrenomedullin in diagnosis and as a biomarker for prognosis, especially in cardiovascular diseases and diabetes. It has also been proposed as a therapeutic agent, as a method to promote regeneration and repair, such as in ischaemic conditions and bone fractures. Conversely, its antagonists or antibodies binding it are claimed to have potential use in blocking angiogenesis in cancers.

Limitations of conventional human basal insulins like NPH have led to the development of more stable and peak less analogs. However, the first generation of basal analogs like glargine and detemir has certain shortcomings which do not allow them to be termed ideal basal insulins. Degludec, a novel basal insulin analog has the potential to overcome these limitations. This paper reviews the potential advantages of degludec over existing basal insulins and analogs. It discusses the basic and clinical studies performed on degludec so far, and highlights the possible role this molecule can play in the management of diabetes mellitus. In this paper, the recent patents on basal insulin have been reviewed so as to provide an insight into the advances in this field. In this article, we present a review of Degludec, as well as related patents.

Last decade had witnessed enormous efforts to develop therapies to treat one or more components of metabolic syndrome, a cluster of diseases including diabetes, obesity and dyslipidemia. Several newer targets are identified and evaluated to treat these metabolic disorders. Microsomal triglyceride transfer protein (MTP) has been identified as one of the promising target for the treatment of dyslipidemia. MTP plays crucial role in the assembly of triglyceride rich chylomicrones in enterocytes and VLDL in hepatocytes and several lines of evidence suggested that MTP inhibitors can be instrumental in combating familial hypercholesterolemia. Several first generation compounds are currently being evaluated in clinic and fatty liver is found to be the main adverse effect of these agents. Recently development of enterocyte specific inhibitor of MTP is emphasized in order to deal with fatty liver issue. In this review, we have dealt with important mechanistic aspects of MTP inhibition, patent scenario and clinical trial outcomes and some of the recent patents related to newly discover chemical scaffolds.

Melatonin is a versatile molecule, synthesized not only by the pineal gland, but also in small amounts by many other organs like retina, gastrointestinal tract, thymus, bone marrow, lymphocytes etc. It plays an important role in various functions of the body like sleep and circadian rhythm regulation, immunoregulatory mechanism, free radical scavenger, antioxidant functions, oncostatic actions, control of reproductive functions, regulation of mood etc. Melatonin has also been found to be effective in combating various bacterial and viral infections. Its administration has been shown to be effective in controlling chlamydial infections, infections induced by Mycobacterium tuberculosis, and also in many viral infections. Molecular mechanisms of anti microbial actions of melatonin have suggested to be due to effects on free radical formation, direct regulation of duplication of bacteria, depletion of intracellular substrates like iron etc. Besides, it is effective in sepsis as demonstrated in various animal models of septic shock. Melatonin's protective action against sepsis is suggested to be due to its antioxidant, immunomodulating and inhibitory actions against the production and activation of pro-inflammatory mediators. Use of melatonin has been beneficial in treating premature infants suffering from severe respiratory distress syndrome and septic shock. It has a potential therapeutic value in treating septic shock and associated multi organ failure in critically ill patients in addition to its antimicrobial and antiviral actions. The patents related to melatonin's use for treatment of bacterial infections and its use in clinical disorders are included.

Omega-3 fatty acids except for their effect on triglycerides levels have cardioprotective properties as well as antiarrhythmic properties.The pleiotropic effects of omega-3 fatty acids, also, include lowering of blood pressure and the favorable effect on endothelial function and high-density cholesterol levels. Furthermore, studies have showed their favorable action in subjects with dementia, Alzheimer's disease and learning disorders. In this paper, a review of the recent patents on omega-3 fatty acids will be presented

During the last 20 years, transgenic constructs based on Adeno Asociated Virus (AAV) have been tested in disease models and proved their efficacy to revert a wide range of pathologies without major side effects. Based on these results, up to 20 clinical trials have been set up to prove therapeutic effect of AAV vectors on neurodegenerative diseases, retinopathies and neuromuscular diseases, among others. It has been shown that AAV vectors support localized long-term, gene expression in the central nervous system, and that restoration of visual function can be achieved in Leber's congenital amaurosis retinopathy. The clinical trials also highlighted new challenges for AAV mediated gene transfer, such as the circumvention of T-cell response to transduced cells. Currently, miniaturized and codon-optimized transgenes, exon skipping cassettes, novel tissue-specific promoters and vector chimeras with tissue-selective tropism are being tested to improve the efficiency and safety of transgene delivery, as required to meet pharmaceutical industry standards. The aim of this review is to revise the latest patents and news on AAV vectors, in order to summarize the state of the art and the potential issues that still need to be faced by pharmaceutical companies for successful gene transfer and commercialization of AAV-based drugs.

Diabetes mellitus (DM) is a metabolic disorder in the endocrine system resulting from a defect in insulin secretion, insulin action or both of them. Adverse side effects of chemical drugs for treatment of diabetes persuaded the using of medical plants. Cherry as a traditionally used plant for treatment of diabetes, is packed with powerful plant pigments called anthocyanins. They give cherries their dark red color and are one of the richest antioxidant sources which lower the blood sugar and bear other beneficial health effects. The purpose of this study is to evaluate the effect of ethanolic extract of cherry fruit on alloxan induced diabetic rats. In this study 36 Male Wistar rats, body weight of 150-200gr were divided into 6 groups. Diabetes was induced by intra peritoneal injection of 120 mg/kg Alloxan. The duration of the cherries treatment was 30 days in which single dose of extracts (200mg/kg) were oral administered to diabetic rats. Blood glucose levels were estimated with glucometer before treatment, 2h and 1- 4 weeks after administration of extracts. Treatment with extracts of the cherries resulted in a significant reduction in blood glucose and urinary microalbumin and an increase in the creatinine secretion level in urea. Extract of this plant is useful in controlling the blood glucose level. Cherries appear to aid in diabetes control and diminution of the complications of the disease. Some relevant patents are also outlined in this article.

Objectives: To study redox responses of cultured osteoblasts, mediated by bacterial lipopolysaccharide (LPS), glucose (G), glucose-oxidised low density lipoprotein (GLDL) and minocycline (M) using radiolabelled steroid markers of redox status and wound healing. The clinical relevance of this concept in periodontitis patients with cardiometabolic risk markers is addressed. Methods: A well differentiated osteoblastic cell-line was cultured in Eagle's MEM in confluent monolayer, in 24 well multiwell plates. Radiolabelled testosterone was used as the steroid substrate. Experiments were set up with controls in the absence of agents, optimal concentrations (previously determined) of G, GLDL, LPS, M, GLDL+LPS and the latter combined with M (n = 8). At the end of a 24h incubation period, the reaction was terminated and the medium analysed for yields of the steroid metabolite 5α-dihydrotestosterone (DHT), the redox marker relevant to wound healing, the weaker androgen 4-androstenedione (4-A) and the diols. Analysis entailed thin layer chromatography and radioisotope scanning. Results: The yields of DHT showed 1.4-fold and 2.3-fold decreases in response to GLDL and LPS respectively and a 1.3-fold reduction in response to the combination, when compared with controls in the absence of agents. Minocycline stimulated the yield of DHT by 1.4-fold, and when combined with GLDL+LPS, the decreased yield was overcome and raised to 2-fold above the combination in response to the addition of minocycline (n = 8; p < 0.001), when compared with controls. The trends in the yields of 4-A and diols were inversely related to each other with increases and decreases over controls respectively, in keeping with enzymic pathways. Conclusions: Decreased yields of the oxidative stress marker DHT in response to LPS, G and GLDL were overcome in the presence of minocycline, which demonstrates its potential role as an adjunctive therapeutic agent in an environment of oxidative stress. These applications could be extrapolated to periodontal disease and co-existing cardiometabolic risk markers, in the context of its antiinflammatory and antioxidant actions relevant to healing. In this paper, recent patents relevant to adjunctive therapeutic management of periodontal disease co-existing with cardiometabolic risk markers are addressed. There have been significant advances in therapeutic interventions for overcoming oxidative stress-inducing mechanisms that are common to these disease entities.

The patents annotated in this section have been selected from various patent databases. These recent patents are relevant to the articles published in this journal issue, categorized by therapeutic areas/targets & therapeutic agents related to endocrine, metabolic and immune drug discovery...